Non insulin-dependent diabetes mellitus (type II diabetes), a debilitating disease characterized by abnormal elevation of blood glucose levels, is driven by three factors: increased hepatic glucose production, inadequate clearance of glucose via insulin mediated pathways, and decreased uptake of circulating glucose by tissues. (Diabetes Review 5(3), 177-269, (1997)). Administration of agents which decrease hepatic glucose production are a fundamental approach to controlling blood glucose levels (Am. J. Physiol. 257, E35-E42 (1989). J. Clin. Endocrinol. Metab. 77, 1180-1183 (1994) and J. Clin. Invest.,92, 2283-2290 (1993)).
Glucocorticoids have been shown to have major influences on glucose production. Glucocorticoid excess aggravates established diabetes and glucocorticoid deficiency reduces blood glucose and improves glucose control in diabetic mice. (Diabetes Review, 1(3), 301-308, (1993). Diabetologia, 9, 376-379 (1973). Horm. Metab. Res., 9, 152-156 (1977)). The underlying mechanism responsible for these effects is believed to be glucocorticoid-induced upregulation of hepatic enzymes required for gluconeogenesis. (Recent Prog. Horm. Res., 26,411-457 (1970). Physiol. Rev., 64, 170-259 (1984). The glucocorticoids are lipid soluble hormones synthesized in the adrenal cortex. They readily pass through cell membranes, enter the cytoplasm of target tissues, and bind to glucocorticoid receptors in the cytoplasm by complexation with heat shock proteins. Upon binding of the hormone to its receptor, the receptor undergoes a conformational change which results in dissociation of heat shock proteins and translocation of the ligand-bound glucocorticoid receptor into the nucleus where it can either initiate or repress specific gene transcription. Transcriptional activation occurs when the ligand bound receptor complex homodimerizes, and the homodimeric receptor ligand complex binds to chromosomal DNA at sequence-specific sites in the promoter region of regulated genes. (Cell, 56, 335-344 (1989). Annu. Rev. Genet., 19, 209-215 (1989)). Among the genes which glucocorticoids up-regulate are those which play key roles in gluconeogenesis and glycogenolysis, particularly PEPCK and glucose-6-phosphatase. (Advanced Enzymology., Meister, Ed. New York, John Wiley and Sons, Inc., 203-281 (1994). and Diabetes 45, 1563-1571 (1996).
Phosphoenolpyruvatecarboxy kinase (PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate into glucose, both of which are required for the synthesis of glucose from oxaloacetate in the liver. Recently, it has been shown that Aventis.RTM. (mifepristone), a potent glucocorticoid receptor (GR) antagonist, reduces mRNA levels of PEPCK and glucose-6-phosphate in the liver and causes a 50% reduction of plasma glucose levels in obese diabetic db/db transgenic mice. (J. Biol. Chem. 272(50), 31475-31481 (1997)). While steroid-based GR antagonists have been useful in demonstrating efficacy for in vivo glucose lowering effects, the utility of such agents is limited due to side effects resulting from potent cross-reactivity with other steroid receptors, in particular progesterone receptor (PR) and mineralocorticoid receptor (MR).
Because agents which function as glucocorticoid antagonists represent a novel approach to controlling type II diabetes, agents which antagonize the glucocorticoid receptor have been the subject of active current research for their clinical potential. Reference is made to U.S. Pat. No. 5,929,058, which discloses a method for treating type II diabetes comprising administering a combination of nonselective steroidal agents exhibiting mineralcorticoid receptor agonist activity and glucocorticoid receptor antagonist activity.
Thus, it would be an important contribution to the art to provide non-steroidal, glucocorticoid-selective agents which antagonize the glucocorticoid receptor. These compounds would be particularly useful for treating type II diabetes and the symptoms thereof, such as hyperglycemia, inadequate glucose clearance, obesity, hyperinsulinemia, hypertriglyceridemia, and high circulating glucocorticoid levels.